Organocatalytic Enantioselective Functionalization of Cyclic α-Hydroxyamides: Access to Chiral Cyclic Imides and Azapolycyclic Compounds.

A highly efficient enantioselective enamine-catalyzed asymmetric conjugate addition has been developed to directly convert unfunctionalized cyclic α-hydroxyamides into chiral cyclic α-hydroxyamides by reacting with vinyl sulfones, which could be used as versatile azacyclic synthons in the following sequences: (1) as the precursors of cyclic N-acyliminium ions to prepare natural productlike chiral azapolycyclic compounds under acidic conditions and (2) to construct chiral cyclic imides bearing unilateral substituents via oxidation reaction-induced formal desymmetrization.

Brønsted-Acid-Catalyzed In Situ Formation of Acyclic Tertiary Enamides and Its Application to the Preparation of Diverse Nitrogen-Containing Heterocyclic Compounds.

A Brønsted acid-catalyzed cascade process, involving in situ formation of acyclic tertiary enamides and intramolecular Michael reaction, is developed for the synthesis of functionalized cyclic tertiary enamides. Based on the dual reactivities of the enamide moiety, several reaction sequences were realized by using rationally designed substrates, leading to biologically relevant nitrogen-containing heterocyclic compounds with diverse structural skeletons in a concise and diastereocontrolled manner.

Cycloartenyl ferulate improves natural killer (NK) cell immunity against cancer by binding to IFNγ receptor 1.

Cycloartenyl ferulate (CF) is abundant in brown rice with multiple biologic functions. It has been reported to possess antitumor activity; however, the related mechanism of action of CF has not been clarified. Herein, we unexpectedly uncover the immunological regulation effects of CF and its molecular mechanism. We discovered that CF directly enhanced the killing capacity of natural killer (NK) cells for various cancer cells in vitro. In vivo, CF also improved cancer surveillance in mouse models of lymphoma clearance and metastatic melanoma dependent on NK cells. In addition, CF promoted anticancer efficacy of the anti-PD1 antibody with improvement of tumor immune microenvironment. Mechanistically, we first unveiled that CF acted on the canonical JAK1/2-STAT1 signaling pathway to enhance the immunity of the NK cells by selectively binding to interferon γ receptor 1. Collectively, our results indicate that CF is a promising immunoregulation agent worthy of attention in clinical application in the future. Due to broad biological significance of interferon γ, our findings also provide a capability to understand the diverse functions of CF.

Acute and 13 weeks subchronic toxicological evaluation of the flavonoid-rich extract of Sophora flavescens.

The roots of Sophora flavescens have a long history of use in Chinese medicine for the treatment of various medical conditions. Flavonoids from the ethyl acetate extract of S. flavescens have shown anti-inflammatory, anticancer, and antidiabetic properties. The objective of this study was to evaluate the toxicological profile of a flavonoid-rich extract of S. flavescens (SFEA). We conducted acute and sub-chronic oral toxicity studies of SFEA in Kunming (KM) mice and Sprague-Dawley (SD) rats. Acute oral administration of 9.0 g/kg SFEA did not result in mortality, clinical signs of toxicity, or abnormal changes in the body weight or food consumption patterns. No significant changes in hematological, blood biochemical, or histopathological parameters were observed. A 13-week sub-chronic toxicity study was conducted in SD rats; the rats were orally administrated with various doses of SFEA (in mg/kg): 0 (control), 40, 80, 400, 800, and 1200. Mortality, clinical signs, or treatment-related changes in body weight, food consumption, hematological parameters, blood biochemical parameters, organ weights, or histopathological parameters were not observed. We found that SFEA is practically nontoxic to KM mice at a dose of 9.0 g/kg and that the no-observed-adverse-effect-level (NOAEL) of SFEA in SD rats is greater than 1200 mg/kg.

Three new cadinane-type sesquiterpenes from Eupatorium adenophorum spreng.

Three new cadinane-type sesquiterpenes, eupatorinones A-C (1-3), along with seven known compounds (4-10), were obtained from the petroleum ether fraction of 95% ethanol extract of Eupatorium adenophorum Spreng. The structures of these new compounds were determined by NMR, MS, and ECD spectra analysis. The configuration of compound 3 was established by quantum chemical calculations of NMR chemical shifts and ECD spectra, that matched the experimental data. In addition, compounds 1, 3 and 5 increased the glucose uptake in L6 cells by 1.42, 1.21 and 1.60 times, respectively.[Formula: see text].

New Polyprenylated Acylphloroglucinol Derivatives and Xanthones From Hypericum wilsonii.

Four new polyprenylated acylphloroglucinol derivatives, hyperwilone A-D (1-4), and two new xanthones, wilsonxanthone A (5) and wilsonxanthone B (6), together with eight known compounds were isolated from the aerial parts of Hypericum wilsonii. Their structures were expounded by comprehensive analysis of the 1D and 2D NMR spectra and HRESIMS. The relative configurations and absolute configurations of 1-6 were determined by NMR calculations and comparing their experimental and computed ECD data. All compounds were evaluated for GLUT4 translocation effects in L6 myotubes. Compound 5 showed the strongest GLUT4 translocation effects with 2.57 folds at a concentration of 30 µg/ml.

Davidone C Induces the Death of Hepatocellular Carcinoma Cells by Promoting Apoptosis and Autophagy.

Davidone C is a newly discovered flavonoid compound purified from the ethyl acetate-soluble fraction of Sophora davidii (Franch.) Skeels. This study explored the anti-tumor activity of davidone C on hepatocellular carcinoma HepG2 and Bel-7402 cells and its mechanism through MTT method, morphological observation, flow cytometry and Western blotting. The results showed that davidone C significantly inhibited the proliferation of HepG2 and Bel-7402 cells in a time- and dose-dependent manner. The morphological changes of apoptotic cells can be observed under an inverted microscope, such as cell floating, chromosome condensation, apoptotic bodies, and other phenomena. The expressions of Bax, cleaved caspase-9, cleaved caspase-3 and cleaved PARP increased with the increase of dosage while Bcl-2 decreased, suggesting that the apoptotic mechanism might be related to the mitochondrial apoptotic pathway. Moreover, davidone C administration can down-regulate the expression of Grp78, and simultaneously up-regulate the expression of caspase-7 and caspase-12, indicating that the apoptotic mechanism might be related to the ERS pathway. In addition, davidone C can down-regulate the expression of p62, and simultaneously up-regulate the expression of LC3-I and LC3-II with a quantitative dependence, suggesting that the mechanism of apoptosis may be related to the autophagy signal pathway. All these results showed davidone C has potential effects on hepatocellular carcinoma.

Davidones F and G, Two Novel Flavonoids from Sophora davidii (Franch.) Skeels.

An unprecedented novel flavanone davidone F (1) with a seven-membered ring side chain, and a novel flavanonol davidone G (2), along with 11 known flavonoids, were isolated from the ethyl acetate fraction of Sophora davidii (Franch.) Skeels. Their planar structures were established by UV, IR, HRESIMS, 1D and 2D NMR data. The relative configurations of 1 and 2 were determined by calculation of NMR chemical shift values, the absolute configuration of 1 and 2 were assigned by comparing their experimental and calculated electronic circular dichroism (ECD) spectra. Moreover, compounds 1-13 were screened for the translocation activity of glucose transporter 4 (GLUT-4), and the fluorescence intensity was increased to the range of 1.56 and 2.79 folds. Compounds 1 and 2 showed moderate GLUT-4 translocation activity with 1.64 and 1.79 folds enhancement, respectively, at a concentration of 20 µg/mL.

Penpolonin A-E, cytotoxic α-pyrone derivatives from Penicillium polonicum.

Five new α-pyrone derivatives, named penpolonin A-E (1-5), together with two known compounds (6-7) were acquired from the endophytic fungus Penicillium polonicum isolated from the roots of Camptotheca acuminata Decne. Their structures were established by combination of NMR and HRESIMS data and the absolute configurations of 1-5 were determined by NMR calculations and comparison of experimental and calculated ECD data. Compounds 3 and 7 exhibited moderate cytotoxicity against Hep-2, TU212 human laryngeal cancer cells with IC50 values ranging from 31.6 to 45.1 µg/ml, compound 4 showed weak cytotoxicity against the Hep-2 and TU212 cell lines with IC50 values of 69.2 and 68.7 µg/ml.

Chemical Constituents from Roots of Sophora davidii (Franch.) Skeels and Their Glucose Transporter 4 Translocation Activities.

Sophora davidii (Franch.) Skeels is a multi-purpose traditional medicine that has long been used for the treatment of various diseases. To discover the potential bioactive composition of S. davidii, a chemical investigation was thus performed. In this research, two new stilbene oligomers, Davidiol E-F (1-2), one new 4-aryl-substituted isoflavan Davidinin A (3), and one new 2-arylbenzofuran dimer, Shandougenine C (4), as well as six known compounds (5-10) were obtained from the ethyl acetate fraction of Sophora davidii (Franch.) Skeels. The structures of new compounds were established by extensive 1D and 2D nuclear magnetic resonance (NMR) spectra with mass spectroscopy data. The absolute configuration of 1-3 was assigned by comparing its experimental and calculated electronic circular dichroism (ECD) spectra. Compounds 1-10 promoted glucose transporter 4 (GLUT-4) translocations by the range of 1.28-2.60 folds, respectively. Compound 9 showed the most potent glucose transporter 4 translocations with 1.60 fold enhancement. The result attained in this study indicated that the separation and characterization of these compounds plays an important role in the research and development of new anti-diabetic drugs and pharmaceutical industry.

Anti-esophageal Cancer Effect of Corilagin Extracted from Phmllanthi Fructus via the Mitochondrial and Endoplasmic Reticulum Stress Pathways.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Corilagin (ß-1-O-galloyl-3,6-(R)-hexahydroxydiphenoyl-d-glucose) is a tannin isolated from the traditional ethnopharmacological plant Phmllanthi Fructus, which is widely used in not only traditional Chinese medicine but also tropical and subtropical medicine to ameliorate various diseases. AIM OF THE STUDY: This study was designed to isolate the potential anti-esophageal cancer (EC) component corilagin from Phmllanthi Fructus and explain its anti-EC mechanism. MATERIALS AND METHODS: Corilagin was isolated from Phmllanthi Fructus by extraction and chromatographic procedures, and its anti-esophageal cancer effect was evaluated by in vitro and in vivo experiments. In vitro experiments included MTT analysis, flow cytometry, and the Transwell assay and were used to observe corilagin-mediated inhibition of EC cell growth. Western blotting was used to analyze the apoptotic pathway of EC cells. In vivo experiments used tumor-bearing nude mice to evaluate the antitumor effect of corilagin, and its potential mechanism was explored by Western blotting. RESULTS: Corilagin showed significant anti-EC activity in vitro and in vivo. Corilagin was significantly cytotoxic to EC cells and induced apoptosis in EC cells. Corilagin induced G0/G1 phase arrest by altering key G0/G1 cell cycle regulatory markers and significantly reducing the migration of EC cells and the number of cells in a time- and dose-dependent manner. Additionally, corilagin inhibited the growth of transplanted tumors in nude mice without significant toxicity. Regarding the anticancer mechanism of corilagin, the results showed that corilagin inhibited esophageal cancer progression by activating mitochondrial and endoplasmic reticulum stress signaling pathways. CONCLUSIONS: Corilagin shows significant anti-EC activity in vitro and in vivo. The mechanism of the anti-EC activity of corilagin may be due to activating mitochondrial and endoplasmic reticulum stress signaling pathways.

New flavonoids from the roots of Sophora davidii (Franch.) Skeels and their glucose transporter 4 translocation activities.

Five new flavanones, davidones A-E (1-5), one new isoflavonoid, cyclolicoisoflavones A3 (8), together with seven known compounds were isolated from the petroleum ether and the ethyl acetate fractions of the roots of Sophora davidii (Franch.) Skeels. The structures of new compounds were established by 1D and 2D NMR and MS data. The absolute configuration of 1-5 was assigned by NMR calculations and comparing its experimental and calculated ECD spectra. Flavanones were the main active principles responsible for the glucose transporter 4 (GLUT-4) translocation activities of SD-PE and SD-EtOAc. Compounds 1-7 and acacetin (12) promoted GLUT-4 translocation by the range of 1.35-3.00 folds, respectively.

Antidiabetic effect of a flavonoid-rich extract from Sophora alopecuroides L. in HFD- and STZ- induced diabetic mice through PKC/GLUT4 pathway and regulating PPARα and PPARγ expression.

HEADINGS ETHNOPHARMACOLOGICAL RELEVANCE: Sophora alopecuroides L. is a traditional ethnopharmacological plant, which is widely used in traditional Chinese medicine and Mongolian and Uighur medicine to ameliorate "thirst disease". AIM OF THE STUDY: This study aimed to investigate the antidiabetic activities and mechanisms of a flavonoid-rich extract from Sophora alopecuroides L. (SA-FRE) both in vivo and vitro. MATERIALS AND METHODS: The main six chemical constituents of SA-FRE were elucidated based on an off-line semi-preparative liquid chromatography nuclear magnetic resonance (LC-NMR) protocol. Myc-GLUT4-mOrange-L6 cell models and mouse model with diabetes induced by high-fat diet combined with STZ injection were respectively adopted to investigate the antidiabetic effects of SA-FRE both in vitro and vivo. RESULTS: In vivo, 4-week treatment of SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance in diabetic mice. Mechanically, SA-FRE regulated PPARα and PPARγ expression in white adipose tissue (WAT) and liver, thereby ameliorating dyslipidemia. Moreover, SA-FRE increased the phosphorylation of PKC and further stimulated the GLUT4 expression in WAT and skeletal muscle, thus increasing the glucose utilization in vivo. In vitro, 50 µg/mL SA-FRE increased GLUT4 translocation to about 1.91-fold and glucose uptake to 1.82-fold in L6-myotubes. SA-FRE treatment increased the GLUT4 expression at both gene and protein levels. Furthermore, only Gö6983, a PKC inhibitor, reversed the SA-FRE-induced GLUT4 translocation and expression at the gene and protein levels. CONCLUSIONS: Generally, SA-FRE ameliorated hyperglycemia, dyslipidemia, and insulin resistance partly through activating PKC/GLUT4 pathway and regulating PPARα and PPARγ expression.

A Simple and Rapid High-Performance Liquid Chromatography-Photodiode Array Method for Quantitation of Triacetin Contents From 30 Batches Produced in China.

In our present study, the standard chemicals of triacetin were purified by reverse-phase and normal-phase semi-preparative high-performance liquid chromatography (HPLC), and 1H NMR and 13C NMR were employed to determine the purity and structure of triacetin. Moreover, a simple and rapid HPLC-photodiode array (PDA) method was developed to determine the contents of triacetin in 30 batches from different suppliers. The chromatographic separation was performed on a Phenomenex Gemini-NX C18 column (250 × 4.6 mm, 5 µm) using a gradient elution system of water and acetonitrile (contained 0.1% of formic acid) solution with a flow rate of 1.0 mL/min at 30°C at 210 nm. Sample preparation method is rapid and energy efficient, and the obtained sample have a good purity. Validation shows good specificity, linearity (R2 = 0.9995), precision, stability, repeatability (% RSD < 2.80) and the average recovery (99.72%) of triacetin. The content of triacetin in most samples is concentrated in 94-97%. This developed approach is simple, rapid, accurate and can be used to quickly determine the purity and the content of triacetin in plasticizers and filter plugs.

Antidiabetic effects of a lipophilic extract obtained from flowers of Wisteria sinensis by activating Akt/GLUT4 and Akt/GSK3ß.

BACKGROUND: Type 2 diabetes mellitus is primarily caused by insulin resistance (IR) in insulin-sensitive tissues, including liver, white adipose tissues (WAT), and skeletal muscles. Discovering nutritious foods with antidiabetic effects is of great significance. Numerous published reports indicated that protein kinase B (Akt) and glucose transporter 4 (GLUT4) play crucial roles in ameliorating IR and diabetic symptoms. OBJECTIVE: In the present study, antidiabetic effects and the potential mechanism of action of WS-PE (a lipophilic extract from edible flowers of Wisteria sinensis) were explored with L6 cells in vitro and in high-fat diet (HFD) + Streptozocin (STZ)-induced diabetic mice in vivo. DESIGN: In vivo, HFD + STZ-induced diabetic mice were used as diabetic models to investigate the potential antidiabetic and antidyslipidemic activities. In vitro, a novel GLUT4 translocation assay system was established to evaluate the potential effects of WS-PE on GLUT4 translocation. Western blot analysis was adopted to investigate the molecular mechanisms of WS-PE both in vivo and in vitro. RESULTS: vitro, WS-PE increased glucose uptake by stimulating GLUT4 expression and translocation, which were regulated by Akt phosphorylation. In vivo, the WS-PE treatment ameliorated the hyperglycemia, IR, and dyslipidemia and reversed hepatic steatosis and pancreatic damage in diabetic mice. The WS-PE treatment increased GLUT4 expression by Akt activation in WAT and skeletal muscle. Akt activation stimulated GSK3ß phosphorylation in liver and skeletal muscles, indicating that WS-PE showed regulatory effects on glycogen synthesis in liver and skeletal muscles. CONCLUSION: These in vitro and in vivo results indicated that the WS-PE treatment exerted antidiabetic effects by activating Akt/GLUT4 and Akt/GSK3ß.

A biflavonoid-rich extract from Selaginella moellendorffii Hieron. induces apoptosis via STAT3 and Akt/NF-κB signalling pathways in laryngeal carcinoma.

Selaginella moellendorffii Hieron. (SM), a perennial evergreen plant, has been used in the treatment of acute infectious hepatitis, thoracic and hypochondriac lumbar contusions, systemic oedema and thrombocytopaenia. However, the role of a biflavonoid-rich extract from SM (SM-BFRE) in anti-larynx cancer has rarely been reported. In this study, the in vitro and in vivo anti-laryngeal cancer activity and potential mechanisms of SM-BFRE were investigated. An off-line semipreparative liquid chromatography-nuclear magnetic resonance protocol was carried out to determine six biflavonoids from SM-BFRE. In vitro, MTT assay revealed that SM-BFRE inhibited the proliferation of laryngeal carcinoma cells. A wound healing assay indicated that SM-BFRE suppressed the migration of laryngeal cancer cells. Hoechst 33 258 and Annexin V-FITC/PI double staining assays were performed and verified that SM-BFRE induced apoptosis in laryngeal carcinoma cells. The Hep-2 bearing nude mouse model confirmed that SM-BFRE also exhibited anticancer effect in vivo. In addition, Western blot analysis demonstrated that SM-BFRE exerted its anti-laryngeal cancer effect by activating the mitochondrial apoptotic pathway and inhibiting STAT3 and Akt/NF-κB signalling pathways. All results suggested that SM-BFRE could be considered as a potential chemotherapeutic drug for laryngeal cancer.

Two new compounds of Penicillium polonicum, an endophytic fungus from Camptotheca acuminata Decne.

To discover novel structural compounds which are producted by endophytic fungi, a primary chemical profiling of Camptotheca acuminata Decne derived endophytic fungus Penicillum polonicum had been taken. Two new compounds ß-lactone polonicin A (1) and enoic acid polonicin B (2) together with seven known compounds 3-9 were isolated from Penicillum polonicum obtained from C. acuminata. The structures of the new compounds 1 and 2 were identified by modern spectrum technology including detailed 1D, 2D NMR and MS data analyses. When tested against HepG2 hepatocellular carcinoma (HCC) cell lines, compounds 4-8 showed moderate anti-HCC activity. In addition, compound 1-3 have effects on increasing GLUT4 translocation and glucose uptake in vitro. Compound 1 showed the strongest glucose uptake and GLUT4 translocation activities in rat skeleton (L6) myoblast cell line with enhancements of 1.8 and 2.1 folds respectively compared to the control.